CN103897026A - Crystal form of bortezomib key intermediate, and preparation method and application of crystal form - Google Patents
Crystal form of bortezomib key intermediate, and preparation method and application of crystal form Download PDFInfo
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Abstract
The invention discloses a novel crystal form of a bortezomib key intermediate II for the first time, provides a novel crystal form of a bortezomib key intermediate, namely (2S)-N-[(1R)-1-(1,2,6,2-dioxo-aza-boron-octane-2-yl)-3-methyl butyl]-3-phenyl-2-pyrazine-2-yl-formamido) propanamide (compound II), namely an alpha crystal form, and discloses a preparation of the compound II, a preparation method of the alpha crystal form, and a method for preparing high-purity bortezomib by using the alpha crystal form intermediate II. The alpha crystal form of the compound II is stable in property, and is conductive to purification of the bortezomib, long-term storage under conventional storage and transportation conditions and especially, development of industrial purification of the bortezomib.
Description
Technical field:
The present invention is specifically related to new crystal of Velcade key intermediate II and preparation method thereof, and uses the new crystal purifying products of Velcade key intermediate II to prepare highly purified Velcade bulk drug product.
Background technology:
Velcade (Bortezomib), trade(brand)name (
ten thousand
) be the new type antineoplastic medicine of Millennium Pharmaceuticals of U.S. research and development, it is a kind of synthetic dipeptides boric acid derivatives, this medicine is 26S proteinase inhibitor, by the degraded of the protein that in blocking-up cell, multiple regulating cell apoptosis and signal conduct, causes death of neoplastic cells.A large amount of research finds, Velcade is to kinds of tumors, the especially multiple myeloma in neoplastic hematologic disorder, and amphicyte type lymphoma and other B cell type lymphomas, Hodgkin lymphoma has stronger anti-tumor activity.In addition, Velcade and chemotherapy drugs in combination application for the treatment of acute myelocytic leukemia, acute lymphoblastic leukemia, adult T Lymphocytic leukemia.Plasmacytic leukemia is all obtained curative effect in various degree, and untoward reaction is less.Difficult point prepared by Velcade bulk drug is (1): bulk drug synthesis technique complexity (2) purifying products difficulty is large, (3) Velcade bulk drug poor stability, and storage and transport condition require harsh.
On the one hand, Velcade purifying difficulty is large.Because the carbon boron chemical bond in Velcade molecular structure is very easily subject to Oxidative demage, very easily there is DeR, generate a large amount of impurity that is difficult to removal, affect the quality of bulk drug, so the effective purification process of exploitation Velcade is the key that this products material medicine is produced.
On the other hand, the poor stability of Velcade bulk drug, the impurity producing in storage transportation has had a strong impact on the quality of bulk drug, causes huge waste.Velcade bulk drug product for current conventional commercial transportation and transport condition be unsettled (conventional commercial transportation and condition of storage, for example higher than the temperature of 23 ° of C and/or be greater than the relative humidity of environment).In the storage and transport condition of Velcade; sometimes must adopt unconventional transport and storage condition; for example; medicine, under the protection of rare gas element, is stored and transported in freezing environment, usually; owing to not accomplishing enough to prepare fully in the transport of medicine and storage process; cause medicine to change, must give up, cause a large amount of wastes.
Velcade molecular structure self is unstable, and unstable equally through the Velcade tricarboxylic anhydride crystal product character that recrystallization obtains repeatedly, carbon boron chemical bond is unstable, easy oxidized fracture.Thereby people attempt to find and obtain the stable precursor compound of Velcade, on the one hand, be conducive to solve the perishable problem of Velcade bulk drug purifying; On the other hand, be conducive to find a kind of novel Velcade storage, transport and the new model using, be, by storage, the stable precursor compound of transport Velcade, changes stable precursor compound into highly purified Velcade by simple method time to be used and uses.
Therefore, find the Velcade key intermediate (being Velcade precursor compound) of stable chemical nature, and be the problem of the extensive concern of medicine industry circle for the product purification purifying of Velcade bulk drug always.Regrettably, the precursor compound of general Velcade is simple boric acid ester compound, all cannot obtain the crystal formation product of stable in properties.In recent years, key intermediate in a Velcade synthesis technique---(2S)-N-[(1R)-1-(1,2,6,2-dioxy azepine boron octane-2-yl)-3-methyl butyl]-3-phenyl-2-pyrazine-2-base formamido-) propionic acid amide (Compound I I) caused people's concern, chemical structure is as shown below:
This compound has description in patent WO2010114982 and WO2011087822, patent has only been pointed out a kind of method of preparing Compound I I, just enumerate the nuclear magnetic resonance data of the structural research of this compound, stable crystal formation and crystallization preparation method is not provided, do not study arranging and the process (being crystallisation process) of formation solid by certain space sequence from Solvation State of this key intermediate, do not study the condition of crystallization, the type of crystallization, and stability features, do not point out the vital role of this compound in Velcade bulk drug purifying.
As everyone knows, material Solvation State forms solid process by certain space sequence arrangement is crystallisation process, this phenomenon extensively exists in organic compound and mineral compound, the organic compound of same chemical structure, because crystallization condition is as solvent, temperature, speed of cooling, the differences such as crystallization speed, while forming crystallization, molecular arrangement is different from crystalline network, may form unformed state, also may form certain crystal habit, cause lattice energy difference, the fusing point of organic compound, dissolution rate, solubleness, the different in kinds such as water absorbability, thereby may affect stability and other performances of this organic compound.
Analysis learns that the structure of Compound I I and general boric acid ester is variant, having the singularity of structure (is in Compound I I molecular structure, except the functional group of boric acid ester, due to the atomic structure characteristic of boron atom electron deficiency, boron atom and nitrogen-atoms close by coordination chemistry bond, make Compound I I there is the characteristic of " molecule inner salt "), its constructional feature determines to obtain the possibility of Compound I I stable crystal form, therefore, be necessary to study the crystallisation process of Compound I I, stable crystal formation and crystallization processes.Be necessary that research prepares the indudstrialized refining purifying process of high purity Velcade by having the Compound I I of stable crystal form simultaneously.
In order to realize above imagination, need the crystallization condition of careful research Compound I I stable crystal form, study the relevant nature of the stable crystal form of Compound I I, and prepare the technique of high purity Velcade by the crystal formation of stable Compound I I.If above imagination becomes a reality, this technique will overcome Velcade bulk drug purifying, huge shortcoming in storage and transport, be conducive to set up the new model of the refining purifying of a kind of brand-new Velcade bulk drug, be conducive to reduce from source the cost of Velcade medicine, manufacture cheap medicine and serve extensive patients.
Summary of the invention:
The object of the invention is to overcome the deficiencies in the prior art, illustrate first the stable crystal form of Velcade key intermediate II, be to provide a kind of Velcade key intermediate---(2S)-N-[(1R)-1-(1, 2, 6, 2-dioxy azepine boron octane-2-yl)-3-methyl butyl]-3-phenyl-2-pyrazine-2-base formamido-) stable crystal form of propionic acid amide (Compound I I), be alpha-crystal form, by a large amount of comparative study, grasp the crystallization condition of this stable crystal form compound, Properties in Stability and other performances, and the alpha-crystal form product that utilizes Compound I I prepares high purity Velcade product.The alpha-crystal form stable in properties of this Compound I I, the utmost point is beneficial to Velcade purification refine, is beneficial to long-term storage under conventional storage and transportation conditions, and the suitability for industrialized production that is beneficial to especially Velcade is carried out.
The present invention relates to the alpha-crystal form of Velcade intermediate (II):
It is characterized in that, the X-ray powder diffraction pattern of described crystal is 6.62,7.03, and 8.71,11.7,21.0,21.6 diffraction angle (2 θ, °) has characteristic peak, and 2 θ of appointment are respectively accurately or within the scope of exact value ± 0.2 °.
The object of the present invention is to provide the preparation method of Compound I I.Be stirring reaction in certain solvent by Compound I and diethanolamine (III), can obtain Compound I I, as shown below:
Wherein R
1, R
2for the alkyl of C1～C10, preferably R
1and R
2be connected to:
or R
1and R
2be connected to respectively hydrogen; Wherein action solvent is selected from ethers, C1～C8 alcohols, C3～C8 ketone, C1～C8 ester class, C5～C8 alkanes, C1～C8 haloalkane hydro carbons, one or more in fragrant alkanes; Described solvent is preferentially selected from: t-butyl methyl ether, ether, tetrahydrofuran (THF), dioxane, methylene dichloride, trichloromethane, tetracol phenixin, acetonitrile, ethylene dichloride, normal hexane, Skellysolve A, normal heptane, ethanol, methyl alcohol, the trimethyl carbinol, propyl carbinol, acetone, butanone, ethyl acetate, toluene, benzene, one or more in dimethylbenzene.
Another object of the present invention is the preparation method of the alpha-crystal form that a kind of Velcade key intermediate (II) is provided, and utilization has the method that alpha-crystal form intermediate II product is prepared Velcade.
The preparation method of alpha-crystal form of the present invention, is characterized in that it comprises as the operation of next step or a few step:
(a) formula II compound is scattered in solvent;
(b) stirring and dissolving under certain temperature, filters insolubles;
(c) filtrate, at certain temperature crystallize out, is filtered crystal;
(d) dry at a certain temperature.
The preparation method of formula II compound alpha-crystal form of the present invention, is characterized in that in step (a), dispersion solvent is selected from ethers, C1～C8 alcohols, C3～C8 ketone, C1～C8 ester class, C5～C8 alkanes, C1～C8 haloalkane hydro carbons, one or more in fragrant alkanes; Described solvent is preferentially selected from: t-butyl methyl ether, ether, tetrahydrofuran (THF), dioxane, methylene dichloride, trichloromethane, tetracol phenixin, acetonitrile, ethylene dichloride, normal hexane, Skellysolve A, normal heptane, ethanol, methyl alcohol, the trimethyl carbinol, propyl carbinol, acetone, butanone, ethyl acetate, toluene, benzene, one or more in dimethylbenzene.
Solvent of the present invention is preferably from ethanol, methyl alcohol, the trimethyl carbinol, propyl carbinol, acetone, ethyl acetate, tetrahydrofuran (THF) and methylene dichloride and mixing solutions thereof.
The preparation method of alpha-crystal form of the present invention, is characterized in that in step (b), solvent temperature is 20～100 ° of C.
The preparation method of alpha-crystal form of the present invention, the temperature control that it is characterized in that step (c) filtrate crystallize out is-10～70 ° of C.
The preparation method of alpha-crystal form of the present invention, is characterized in that the dry temperature of step (d) is 0～100 ° of C.
The purposes of the alpha-crystal form of Compound I I of the present invention, is characterized in that, described purposes refers to that the alpha-crystal form of Compound I I, in certain acid system, prepares Velcade under certain temperature condition:
The alpha-crystal form of use Compound I I of the present invention is prepared Velcade, it is characterized in that, described acid system comprises hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid; Described range of reaction temperature is 0～100 ° of C.
The invention discloses a kind of boric acid ester deprotection and prepare the technique of high purity Velcade (route one), first preparation has the key intermediate II of stable alpha crystal formation, then, prepares highly purified Velcade by simple deprotection reaction.Document CN201110300750, the patents such as CN201210147057 and CN200580017645 adopt toxic substance (isobutyl-boric acid) through boric acid ester exchange, and recrystallization is prepared Velcade (route two) repeatedly.
The present invention's (route one) prepares positively effect and the unformed intermediate II that alpha-crystal form key intermediate II brings for Velcade purification, simultaneously and other open source literatures (route two) relatively, as following table:
| The patent No. | Alpha-crystal form of the present invention | Unformed | CN201110300750 | CN201210147057 | CN200580017645 |
| Refining productive rate | >90％ | >90％ | 40％～60％ | 67％ | 70％ |
| Purity | >99％ | 90％ | 90％ | 94％ | 97％ |
The present invention, by first preparing the intermediate II with stable alpha crystal formation, then prepares highly purified Velcade by simple deprotection reaction, and refining total recovery reaches 90%, and the purity of Velcade reaches more than 99%; And prepare Velcade by armorphous intermediate II, purity only can reach 90%; Other known references CN201110300750, the patent such as CN201210147057 and CN200580017645, its overall yield is only 40%～60%, disclosed by the invention, prepare Velcade by the intermediate II with stable alpha crystal formation, aspect total recovery and purity, be all better than existing literature method.
The alpha-crystal form stable in properties of the key intermediate II of the Velcade that the present invention prepares, under conventional preservation and storage condition, crystal formation and quality have no significant change, and now stability test result of study are summarized as follows.Stability conditions: get respectively and there is alpha-crystal form Velcade key intermediate II and be numbered respectively in right amount B1, B2, the unformed powder B4 of B3 and Velcade key intermediate II, (illumination under following condition respectively, high temperature and high humidity) carry out stability test, test-results is summed up as following table:
Can find out to have alpha-crystal form Velcade key intermediate II at high temperature by above stability test, under the storage condition of high humidity, its related substance is without obvious increase, and crystal formation does not change, and still keeps the state of stable alpha-crystal form.The influence factor test-results of carrying out under the irradiation of high light shows, related substance slightly increases, and crystal formation slightly changes, and therefore advises that alpha-crystal form Velcade key intermediate II keeps in Dark Place.In above influence factor test, all carry out comparative study with the unformed powder of Velcade key intermediate II, under above test condition, the related substance of unformed powder all has increase, the character that unformed powder is described is extremely unstable, is unfavorable for the preservation of this intermediate.
A kind of alpha-crystal form Velcade key intermediate II stable in properties provided by the invention, tool following points progress in the industrialization of Velcade production of raw medicine is used:
(1), alpha-crystal form Velcade key intermediate II stable in properties in recrystallization process, be conducive to the purifying of Velcade, in recrystallization process, can not introduce new degradation impurity.Alpha-crystal form Velcade key intermediate II carbon boron Bonding Properties is stable, and in the operation of recrystallization repeatedly, stable in properties, is easy to crystallization, does not substantially have new degradation impurity to occur.
(2), alpha-crystal form Velcade key intermediate II is by the processing of simple acidifying deprotection, can high yield obtain highly purified Velcade rice bulk drug product (productive rate reaches more than 90, and product purity reaches more than 99%).Alpha-crystal form Velcade key intermediate II, through simple deprotection operation (room temperature reaction condition, the reaction times is short, referring to embodiment 14～18), can high yield obtain high purity Velcade.
(3), alpha-crystal form Velcade key intermediate II stable in properties, be easy to storage and transport, simple operations can obtain the former bulk drug product of high purity Velcade, a brand-new Velcade storage is provided and has used new model.Alpha-crystal form Velcade key intermediate II stable in properties (referring to relevant stability study data in specification sheets), can high yield obtain highly purified Velcade bulk drug by simple deprotection processing.Therefore; unstable in view of Velcade bulk drug character, Velcade can be preserved with the state with alpha-crystal form Velcade key intermediate II, need to use time; through the simple deprotection processing of a step, just can high yield obtain highly purified Velcade bulk drug for.The novel storage of this Velcade and use pattern, overcome the shortcoming of the storage transport condition (protection of inert gas, cold condition) of Velcade harshness.
Brief description of the drawings:
Fig. 1 is the powder diagram of the alpha-crystal form of the Compound I I for preparing of the present invention.
Fig. 2 is the high-efficient liquid phase chromatogram of the high purity Velcade for preparing in embodiment 10.
Embodiment:
Further illustrate the present invention with embodiment below, but the present invention is not limited.
The preparation of Velcade key intermediate II:
Digest compound Ia (according to document J.Am.Chem.Soc.2008 by 4.6,130,6910-6911 preparation) be dissolved in ethyl acetate, add 2.6 grams of diethanolamine, in stirring at room temperature 12 hours, there is a large amount of solids to separate out, filter and obtain Compound I I crude product, obtain the 4.0 α type crystal formation products (productive rate 88.4%) that digest compound II with ethyl acetate washing leaching cake.
Embodiment 2
5.2 grams of compounds ibs (according to patent CN200580017645 preparation) are dissolved in methyl alcohol, add 2.6 grams of diethanolamine, in stirring at room temperature 24 hours, there is a large amount of solids to separate out, filtration obtains Compound I I crude product, obtains the 4.4 α type crystal formation products (productive rate 97.3%) that digest compound II with methanol wash filter cake.
Digesting compound Ic (according to patent CN201210147057 preparation) by 4.5 is dissolved in t-butyl methyl ether, add 2.6 grams of diethanolamine, in stirring at room temperature 24 hours, there is a large amount of solids to separate out, filtration obtains Compound I I crude product, obtains the 4.2 α type crystal formation products (productive rate 92.9%) that digest compound II with t-butyl methyl ether washing leaching cake.
Embodiment 4
By 3.8 grams of Velcades (Id) crude product (according to document Tetrahedron, 2009,65,7105-7108 preparation) be dissolved in ethyl acetate, add 2.6 grams of diethanolamine, in stirring at room temperature 24 hours, have a large amount of solids to separate out, filtration obtains Compound I I crude product, obtains the 4.5 α type crystal formation products (productive rate 99.5%) that digest compound II with ethyl acetate washing leaching cake.
The preparation of the alpha-crystal form of Velcade key intermediate II:
Embodiment 5
Digest compound II by 5 and be scattered in the ethanol of 50mL, reflux 30 minutes in 80 ° of C, filter a small amount of insolubles, filtrate lets cool to room temperature, waits to separate out a large amount of crystal, filters crystal, dry under 30 ° of C conditions, obtains alpha-crystal form Velcade key intermediate II.
Embodiment 6
Digest compound II by 5 and be scattered in the methyl alcohol of 50mL, reflux 60 minutes in 60 ° of C, filter a small amount of insolubles, filtrate lets cool to 0 ° of C, waits to separate out a large amount of crystal, filters crystal, dry under 50 ° of C conditions, obtains alpha-crystal form Velcade key intermediate II.
Embodiment 7
Digest compound II by 5 and be scattered in the trimethyl carbinol of 50mL, reflux 30 minutes in 100 ° of C, filter a small amount of insolubles, filtrate lets cool to room temperature, waits to separate out a large amount of crystal, filters crystal, dry under 25 ° of C conditions, obtain alpha-crystal form Velcade key intermediate II.
Digesting compound II by 5 is scattered in the acetone of 100mL, reflux 60 minutes in 50 ° of C, filter a small amount of insolubles, filtrate lets cool to-10 ° of C, waits to separate out a large amount of crystal, filters crystal, place crystal in freeze drier pallet, controlling temperature is under 0 ° of C condition, vacuumizes dry 2 hours, obtains alpha-crystal form Velcade key intermediate II.
Digest in the ethyl acetate that compound II is scattered in 100mL 5, reflux 60 minutes in 60 ° of C, filter a small amount of insolubles, filtrate lets cool to 40 ° of C, waits to separate out a large amount of crystal, filters crystal, dry under 50 ° of C conditions, obtain alpha-crystal form Velcade key intermediate II.
Digest compound II by 5 and be scattered in the tetrahydrofuran (THF) of 50mL, reflux 30 minutes in 70 ° of C, filter a small amount of insolubles, filtrate lets cool to room temperature, waits to separate out a large amount of crystal, filters crystal, dry under 30 ° of C conditions, obtain alpha-crystal form Velcade key intermediate II.
Embodiment 11
Digest compound II by 5 and be scattered in the methylene dichloride of 100mL, reflux 60 minutes in 50 ° of C, filter a small amount of insolubles, filtrate lets cool to room temperature, waits to separate out a large amount of crystal, filters crystal, dry under 30 ° of C conditions, obtain alpha-crystal form Velcade key intermediate II.
Embodiment 12
Digesting compound II by 5 is scattered in the methylene dichloride and methyl alcohol (1: 1) mixed solvent of 100mL, reflux 60 minutes in 60 ° of C, filter a small amount of insolubles, filtrate lets cool to room temperature, wait to separate out a large amount of crystal, filter crystal, dry under 35 ° of C conditions, obtain alpha-crystal form Velcade key intermediate II.
Embodiment 13
Digesting compound II by 5 is scattered in the methylene dichloride and ethanol (1: 1) mixed solvent of 100mL, reflux 30 minutes in 70 ° of C, filter a small amount of insolubles, filtrate lets cool to room temperature, wait to separate out a large amount of crystal, filter crystal, dry under 30 ° of C conditions, obtain alpha-crystal form Velcade key intermediate II.
The alpha-crystal form product of Velcade key intermediate II is converted into high purity Velcade:
Embodiment 14
5 grams of the alpha-crystal form products of Velcade key intermediate II are placed in to the round-bottomed flask of 100mL, add 30mL methyl alcohol to disperse, then under room temperature condition, be added dropwise to the dilute hydrochloric acid (2mol/mL) of 10mL, under room temperature condition, react approximately 1 hour, with 100mL ethyl acetate dispersion reaction solution, and with three times (50mL × 3) of saturated sodium bicarbonate washing, after use saturated common salt water washing three times (50mL × 3), combined ethyl acetate layer, anhydrous sodium sulfate drying, is concentrated into about 40mL.Place room temperature, have a large amount of crystal to occur, filter crystal, be drying to obtain high purity Velcade.(productive rate 95%, purity 99.96%)
1h NMR (400MHz, CD
3oD): δ 9.17 (s, 1H), 8.79 (s, 1H), 8.69 (s, 1H), 7.30～7.23 (m, 5H), 5.03 (t, J=7.6Hz, 1H), 3.26～3.23 (t, J=6.1Hz, 2H), 2.70～2.66 (t, J=7.6Hz, 1H), 1.43～1.35 (m, 1H), 1.21～1.17 (t, J=7.0Hz, 2H), 0.85～0.83 (m, 6H);
13c NMR (100M Hz, CD
3oD): δ 176.9,165.2,148.9,145.6,144.8,137.1,130.6,129.8,128.3,52.9,40.9,38.6,26.7,23.8,22.1.
Embodiment 15
5 grams of the alpha-crystal form products of Velcade key intermediate II are placed in to the round-bottomed flask of 100mL, add 30mL ethanol to disperse, then under 0 ° of C condition, be added dropwise to the dilute sulphuric acid (2mol/mL) of 5mL, under room temperature condition, react approximately 1.5 hours, with 100mL ethyl acetate dispersion reaction solution, and with three times (50mL × 3) of saturated sodium bicarbonate washing, after use saturated common salt water washing three times (50mL × 3), combined ethyl acetate layer, anhydrous sodium sulfate drying, is concentrated into about 40mL.Place room temperature, have a large amount of crystal to occur, filter crystal, be drying to obtain high purity Velcade.(productive rate 90%, purity >99%)
Embodiment 16
5 grams of the alpha-crystal form products of Velcade key intermediate II are placed in to the round-bottomed flask of 100mL, add 30mL methyl alcohol to disperse, then under room temperature condition, be added dropwise to rare nitric acid (2mol/mL) of 10mL, under room temperature condition, react approximately 2 hours, with 100mL ethyl acetate dispersion reaction solution, and with three times (50mL × 3) of saturated sodium bicarbonate washing, after use saturated common salt water washing three times (50mL × 3), combined ethyl acetate layer, anhydrous sodium sulfate drying, is concentrated into about 40mL.Place room temperature, have a large amount of crystal to occur, filter crystal, be drying to obtain high purity Velcade.(productive rate 92%, purity >99%)
Embodiment 17
5 grams of the alpha-crystal form products of Velcade key intermediate II are placed in to the round-bottomed flask of 100mL, add 30mL methyl alcohol to disperse, then under 60 ° of C conditions, be added dropwise to the dilute phosphoric acid (2mol/mL) of 10mL, under room temperature condition, react approximately 4 hours, with 100mL ethyl acetate dispersion reaction solution, and with three times (50mL × 3) of saturated sodium bicarbonate washing, after use saturated common salt water washing three times (50mL × 3), combined ethyl acetate layer, anhydrous sodium sulfate drying, is concentrated into about 40mL.Place room temperature, have a large amount of crystal to occur, filter crystal, be drying to obtain high purity Velcade.(productive rate 96%, purity >99%)
Embodiment 18
5 grams of the alpha-crystal form products of Velcade key intermediate II are placed in to the round-bottomed flask of 100mL, add 30mL methyl alcohol to disperse, then under 80 ° of C conditions, be added dropwise to the dilute acetic acid (2mol/mL) of 10mL, under room temperature condition, react approximately 5 hours, with 100mL ethyl acetate dispersion reaction solution, and with three times (50mL × 3) of saturated sodium bicarbonate washing, after use saturated common salt water washing three times (50mL × 3), combined ethyl acetate layer, anhydrous sodium sulfate drying, is concentrated into about 40mL.Place room temperature, have a large amount of crystal to occur, filter crystal, be drying to obtain high purity Velcade.(productive rate 94%, purity >99%)
Claims (10)
1. the α type crystal formation of a compound as shown in figure below molecular formula II:
It is characterized in that, the X-ray powder diffraction pattern of described crystal is 6.62,7.03, and 8.71,11.7,21.0,21.6 diffraction angle (2 θ, °) has characteristic peak, and 2 θ of appointment are respectively accurately or within the scope of exact value ± 0.2 °.
2. as a preparation method for figure below molecular formula II compound, the stirring reaction in certain solvent by Compound I and diethanolamine (III), can obtain Compound I I, as shown below:
Wherein R
1, R
2for the alkyl of C1～C10, preferably R
1and R
2be connected to:
or R
1and R
2be connected to respectively hydrogen; Wherein action solvent is selected from ethers, C1～C8 alcohols, C3～C8 ketone, C1～C8 ester class, C5～C8 alkanes, C1～C8 haloalkane hydro carbons, one or more in fragrant alkanes; Described solvent is preferentially selected from: t-butyl methyl ether, ether, tetrahydrofuran (THF), dioxane, methylene dichloride, trichloromethane, tetracol phenixin, acetonitrile, ethylene dichloride, normal hexane, Skellysolve A, normal heptane, ethanol, methyl alcohol, the trimethyl carbinol, propyl carbinol, acetone, butanone, ethyl acetate, toluene, benzene, one or more in dimethylbenzene.
3. a preparation method for α type crystal formation as claimed in claim 1, is characterized in that comprising as the operation of next step or a few step:
(a) formula II compound is scattered in solvent;
(b) stirring and dissolving under certain temperature, filters insolubles;
(c) filtrate, at certain temperature crystallize out, is filtered crystal;
(d) dry at a certain temperature.
4. the preparation method of formula II compound α type crystal formation as claimed in claim 3, it is characterized in that in step (a), dispersion solvent is selected from ethers, C1～C8 alcohols, C3～C8 ketone, C1～C8 ester class, C5～C8 alkanes, C1～C8 haloalkane hydro carbons, one or more in fragrant alkanes; Described solvent is selected from: t-butyl methyl ether, ether, tetrahydrofuran (THF), dioxane, methylene dichloride, trichloromethane, tetracol phenixin, acetonitrile, ethylene dichloride, normal hexane, Skellysolve A, normal heptane, ethanol, methyl alcohol, the trimethyl carbinol, propyl carbinol, acetone, butanone, ethyl acetate, toluene, benzene, one or more in dimethylbenzene.
5. solvent as claimed in claim 4 is preferentially selected from ethanol, methyl alcohol, the trimethyl carbinol, propyl carbinol, acetone, ethyl acetate, tetrahydrofuran (THF) and methylene dichloride and mixing solutions thereof.
6. the preparation method of α type crystal formation as claimed in claim 3, is characterized in that in step (b), solvent temperature is 20～100 ° of C.
7. the preparation method of α type crystal formation as claimed in claim 3, the temperature control that it is characterized in that filtrate crystallize out in step (c) is-10～70 ° of C.
8. the preparation method of α type crystal formation as claimed in claim 3, is characterized in that temperature dry in step (d) is 0～100 ° of C.
9. a purposes for the α type crystal formation of Compound I I as claimed in claim 1 or 2, is characterized in that, described purposes refers to that the α type crystal formation of Compound I I, in certain acid system, prepares Velcade under certain temperature condition:
10. the α type crystal formation of use Compound I I as claimed in claim 1 is prepared Velcade, it is characterized in that, described acid system comprises hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid; Described range of reaction temperature is 0～100 ° of C.
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|---|---|---|---|
| CN201210589521.6A CN103897026A (en) | 2012-12-29 | 2012-12-29 | Crystal form of bortezomib key intermediate, and preparation method and application of crystal form |
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| CN201210589521.6A CN103897026A (en) | 2012-12-29 | 2012-12-29 | Crystal form of bortezomib key intermediate, and preparation method and application of crystal form |
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| CN107001275A (en) * | 2014-09-26 | 2017-08-01 | 赫尔辛医疗股份公司 | The crystal formation of the antagonists of NK 1 |
| US10144761B2 (en) | 2015-06-19 | 2018-12-04 | Hanlin Scientific Inc. | Chiral specific boron-containing compounds and their use in treating cancer or amyloidosis |
| CN110642881A (en) * | 2019-10-18 | 2020-01-03 | 扬子江药业集团上海海尼药业有限公司 | Bortezomib crystal form M and preparation method and application thereof |
| CN111116711A (en) * | 2018-11-01 | 2020-05-08 | 博谦生技股份有限公司 | Method for preparing bortezomib and intermediate product and crystalline form thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107001275A (en) * | 2014-09-26 | 2017-08-01 | 赫尔辛医疗股份公司 | The crystal formation of the antagonists of NK 1 |
| US10144761B2 (en) | 2015-06-19 | 2018-12-04 | Hanlin Scientific Inc. | Chiral specific boron-containing compounds and their use in treating cancer or amyloidosis |
| US11325942B2 (en) | 2015-06-19 | 2022-05-10 | Beijing Artivila Biopharma Co. Ltd. | Chiral specific boron-containing compounds and their use in treating cancer or amyloidosis |
| CN111116711A (en) * | 2018-11-01 | 2020-05-08 | 博谦生技股份有限公司 | Method for preparing bortezomib and intermediate product and crystalline form thereof |
| CN110642881A (en) * | 2019-10-18 | 2020-01-03 | 扬子江药业集团上海海尼药业有限公司 | Bortezomib crystal form M and preparation method and application thereof |
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